M: The CB(1) cannabinoid receptor is coupled to the activation of c-Jun Nterminal kinase

Cannabinoids exert most of their effects through the CB1 recep-tor. This G-protein-coupled receptor has been shown to be func-tionally coupled to inhibition of adenylyl cyclase, modulation of ion channels, and activation of extracellular signal-regulated kinase. Using Chinese hamster ovary cells stably transfected with the CB1 receptor cDNA, we show here that D9-tetrahydrocannabinol (THC), the major active component of marijuana, induces the activation of c-Jun N-terminal kinase (JNK). Western blot analysis showed that both JNK-1 and JNK-2 were stimulated by THC. The effect of THC was also exerted by endogenous cannabinoids (anandamide and 2-arachidonoylglycerol) and synthetic cannabi-noids (CP-55,940, HU-210, and methanandamide), and was pre-vented by the selective CB1 antagonist SR141716. Pertussis toxin, wortmannin, and a Ras farnesyltransferase inhibitor peptide blocked, whereas mastoparan mimicked, the CB1 receptor-evoked activation of JNK, supporting the involvement of a Gi/Go-protein, phosphoinositide 39-kinase and Ras. THC-induced JNK stimulation was prevented by tyrphostin AG1296, pointing to the implication of platelet-derived growth factor receptor transactiva-tion, and was independent of ceramide generation. Experiments performed with several types of neural cells that endogenously express the CB1 receptor suggested that long-term JNK activa-tion may be involved in THC-induced cell death. The CB1 canna-binoid receptor was also shown to be coupled to the activation of p38 mitogen-activated protein kinase. Data indicate that activa-tion of JNK and p38 mitogen-activated protein kinase may be responsible for some of the cellular responses elicited by the CB1 cannabinoid receptor. Cannabinoids, the active components of Cannabis sativa (marijuana) and their endogenous counterparts, exert most of their central and peripheral effects by binding to specifi